Real-world experience and clinical research converge in demonstrating that substance-dependent individuals will continue to use drugs despite an often strong desire to cease taking them. This suggests that a cardinal characteristic of dependency may be reduced ability to manage goal-directed behavior in situations when drug- related rewards are available. Current models of cocaine addiction have proposed that cocaine may alter the sensitivity of mesocorticolimbic reward circuitry to drug- and nondrug-rewards, such that chronic cocaine users manifest increased sensitivity to drug-related rewards, yet decreased sensitivity to other nondrug rewards. Decreased responsiveness to nondrug rewards may lead to a state of reduced reward, characterized by decreased pleasure for, and decreased goal-direction towards, nondrug rewards. Within this framework, the dependent individual's constant craving for cocaine may be interpreted as a desire to alleviate this chronic state of hypo-reward, while their drug-taking behavior may be interpreted as a direct attempt to reactivate this desensitized reward circuitry. One implication of this perspective is that the ability to recalibrate these altered reward sensitivities may serve as a viable treatment strategy for individuals with serious cocaine dependency. Emerging technology, such as real-time functional magnetic resonance imaging (rt-fMRI), affords the opportunity to provide individuals with online feedback regarding the current state of their neural activity. One valuable use of this technology may be to provide cocaine-dependent individuals with information regarding their neural response to drug-related and nondrug-related reward, and to utilize this "neuro-feedback" approach to train participants to gain control over their neural activity, and to rebalance altered reward sensitivities. Our team of investigators has over two decades of collective experience working with substance abusing populations, and has provided substantive data demonstrating the feasibility rt-fMRI as a technology capable of supporting the voluntary modulation of neural responses. Here, we propose to utilize the R21 mechanism to collect data that will demonstrate the specific feasibility of this technology within a substance abusing population. To this end, we aim to collect rt-fMRI data on 60 cocaine-dependent individuals. These pparticipants will be presented with a series of picture stimuli displaying drug-related and nondrug-related rewards, and will be asked to increase (to the nondrug-related rewards), and decrease (to the drug-related rewards), their neural response in the nucleus accumbens, a primary site of reward-related processing. Evidence that substance abusers can modulate their neural response within nucleus accumbens can serve as a critical step towards development of comprehensive rt-fMRI-based treatment programs for substance abuse, and can serve as a gateway for future work to achieve these treatment goals. To this end, our team anticipates the data derived from this R21-based protocol to serve as important support for larger-scale research projects aimed at tailored rt-fMRI treatment programs for substance abuse disorders. PUBLIC HEALTH RELEVANCE: Recent models of substance dependence argue that the substance abuser may experience decreased neural activity in response to nondrug rewards, yet increased neural activity in response to drug rewards. The present study will test the feasibility of utilizing real-time functional magnetic resonance imaging (rt-fMRI) to provide real-time neurofeedback as a technique for facilitating voluntary modulation of reward-related neural activity in healthy, as well as cocaine-dependent, populations. The ability to use real-time neurofeedback to modulate altered sensitivity to reward may prove a viable treatment option for substance abuse disorders. The present work will provide a fundemental evaluation of this emerging technology, and will serve as a gateway for future work to conduct larger-scale clinical studies of rt-fMRI in substance-abusing populations.